Although antiestrogens are known to be effective against many metastatic breast cancers and the antiestrogen tamoxifen has now been approved for general clinical use, little is known of their mechanism of action beyond the fact that they mimic estradiol in binding cytoplasmic estrogen receptor and translocating it to the cell nucleus. We therefore propose to compare selected antiestrogens with active estrogens at four critical steps of estrogen action: 1) temperature-dependent estrogen-induced receptor transformation; 2) receptor translocation and retention in cell nuclei; 3) receptor binding to specific nuclear acceptor sites; 4) nuclear processing, the depletion of receptor from the nucleus. Three model systems will be compared: the normal rat and mouse uterus, the DMBA-induced rat mammary tumor system, and the MCF-7 human breast cancer cell line. The goal will be discovery of the critical differences between estrogen and antiestrogen action, particularly in mammary tumor cells and particularly as correlated with tumor responsiveness to antiestrogen therapy.